Over the last ten years, the highly efficient anti-microbial response of the fruit fly Drosophila has evolved as one of the most powerful biological models to study innate immunity. A hallmark of this response is the challenge-induced expression of potent anti-microbial peptides that counter invading microorganisms. The identity of these molecules has now been established and two signaling pathways leading to their immune-controlled expression have been identified and worked out in significant detail. The last frontier in our understanding of this pristine host defense is the recognition of infectious microorganisms and the molecular mechanisms that link this recognition to activation of the pathways that ultimately lead to expression of the immune response genes. Several families of proteins have been identified recently which may serve as recognition proteins, namely the PGRPs (Peptidoglycan Recognition Proteins), GNBPs (Gram-Negative Binding Proteins) and some of the Thioester Containing Proteins (TEPs). The Aim of the Project is to combine methods of molecular genetics, biochemistry, structural biology and cell biology to elucidate the precise mechanisms by which these recognition proteins and others which remain to be identified, sense microbial patterns and how this interaction translates into activation of intracellular signaling in immune-responsive cells. This Project is crucially dependent on close interactions-both conceptual and methodological- with our partners working on the same central questions in mosquitoes (the Kafatos Laboratory Project 4) and mammals (the Ezekowitz Laboratory, Project 1). Indeed, some of the proposal Aims can only be addressed in collaboration between our groups and through complementing our respective expertise and facilities.